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Objective To investigate the diagnostic accuracy of endometrial biopsy performed with hysteroscopic direct visualization using the “grasp technique” for the detection of endometrial carcinoma (EC) histology type and tumor grade. Methods A cross-sectional study including the clinical and pathology records of patients with confirmed EC who underwent definitive surgery at University of Naples was performed. The preoperative diagnosis of endometrial tumor type and grade obtained using the hysteroscopy grasp technique was correlated with the final pathology specimens. Those results were compared to the diagnostic accuracy of the biopsies collected in a cohort of patients who underwent preoperative diagnostic hysteroscopy followed by blind endometrial biopsy using the Novak curette with subsequent surgical definitive treatment at University of Pisa. Statistical analysis was based on frequency data and diagnostic agreement of the pathology results. Results A total of 129 patients were included in the final analysis. An agreement rate of 104/106 (98.1%) for endometrioid type and 15/23 (65.2%) for non-endometrioid type was obtained between preoperative hysteroscopic grasp endometrial biopsy specimens and the final pathology with a coefficient k for G1, G2 and G3 tumors of 0.928, 0.925 and 0.974, respectively. When compared to 121 patients undergoing preoperative blind Novak endometrial biopsy, the hysteroscopic grasp technique was superior in agreement rates for tumor histotype [diagnostic accuracy (0.922 vs 0.890); K value (0.705 vs 0.642)] and grade when in presence of endometrioid type EC (K Cohen 0.354 for G1, 0.263 for G2 and 0.488 for G3). Conclusions Preoperative hysteroscopic guided “grasp” endometrial biopsy provides a more accurate diagnosis of EC histology type and tumor grade when in presence of endometrioid type tumor compared to blind endometrial biopsy obtained using the Novak curette.

BACKGROUND: Estetrol (E4) is a natural estrogen produced solely during human pregnancy. E4 is suitable for clinical use since it acts as a selective estrogen receptor modulator. In clinical trials E4 has been seen to have little or no effect on coagulation. Hence, it is interesting to investigate whether E4 alters endothelial-dependent fibrinolysis. OBJECTIVES: We studied the effects of E4 on the fibrinolytic system and whether this could influence the ability of endothelial cells to migrate. In addition, we compared the effects of E4 with those of 17β-estradiol (E2). STUDY DESIGN: Human umbilical vein endothelial cells (HUVEC) were obtained from healthy women. Expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) proteins was evaluated by Western blot analysis. Endothelial cell migration was studied by razor-scrape horizontal and multiwell insert systems assays. RESULTS: E4 increased the expression of t-PA, u-PA and PAI-1 in HUVEC, but less so than did equimolar amounts of E2. The effects of E4 on t-PA, u-PA and PAI-1 were mediated by the induction of the early-immediate genes c-Jun and c-Fos. E4 in combination with E2 antagonized the effects induced by pregnancy-like E2 concentrations but did not impair the effects of postmenopausal-like E2 levels. We also found that the increased synthesis of PAI-1, u-PA and t-PA induced by E2 and E4 is important for horizontal and three-dimensional migration of HUVEC. CONCLUSIONS: These results support the hypothesis that E4 acts as an endogenous selective estrogen receptor modulator (SERM), controlling the fibrinolytic system and endothelial cell migration. Fil: Montt Guevara, Maria Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Università degli Studi di Pisa; Italia Fil: Palla, Giulia. Università degli Studi di Pisa; Italia Fil: Spina, Stefania. Università degli Studi di Pisa; Italia Fil: Bernacchi, Guja. Università degli Studi di Pisa; Italia Fil: Cecchi, Elena. Università degli Studi di Pisa; Italia Fil: Campelo, Adrián Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; Argentina. Università degli Studi di Pisa; Italia Fil: Shortrede, Jorge Eduardo. Università degli Studi di Pisa; Italia Fil: Canu, Alessio. Università degli Studi di Pisa; Italia Fil: Simoncini, Tommaso. Università degli Studi di Pisa; Italia

Introduction: We present a case of posterior deep infiltrating endometriosis with intrinsic ureteral involvement in a 43-year-old patient treated by robot-assisted laparoscopic technique. To our knowledge, this is the second case of robot-assisted ureteroneocystostomy with concomitant hysterectomy reported in the literature1–5, yet the first one to be described with a video presentation. Case description: A 43-year-old woman with a past history of endometriosis treated laparoscopically was referred to our clinic for grade II–III left hydronephrosis. Pelvic ultrasound and magnetic resonance imaging demonstrated a 3-cm paracervical endometriotic nodule causing ureteral compression, another 1.6-cm endometriotic nodule at the rectosigmoid junction, an adenomyotic nodule in the anterior uterine wall, and an endometrioma on the right ovary. Given that the patient had an absolute contraindication to hormonal therapy, we opted for robot-assisted laparoscopic complete eradication of endometriosis. The procedure consisted in total hysterectomy with concomitant removal of the rectovaginal nodule, right adnexectomy, left salpingectomy, and left ureteral resection with ureteroneocystostomy. After 8 days, a cystography was accomplished to confirm anastomosis integrity, and the bladder catheter was removed. The patient was discharged on day 8 after a regular postoperative period. One year after the surgery, the patient refers wellbeing. Conclusion: The robotic approach in such a complex procedure as surgical treatment of ureteral and deep infiltrating endometriosis is feasible and safe with acceptable postoperative outcome. Further investigations with larger comparative cohorts that include cost analysis are needed to fully assess the benefits achieved by robotic assistance in patients with ureteral and deep infiltrating endometriosis.

3,5-diiodo-L-thyronine (3,5-T2) is an endogenous derivative of thyroid hormone with potential metabolic effects. It has been detected in human blood by immunological methods, but a reliable assay based on mass spectrometry (MS), which is now regarded as the gold standard in clinical chemistry, is not available yet. Therefore, we aimed at developing a novel ad-hoc optimized method to quantitate 3,5-T2 and its isomers by MS in human serum. Serum samples were obtained from 28 healthy subjects. Two ml of serum were deproteinized with acetonitrile and then subjected to an optimized solid phase extraction-based procedure. To lower background noise, the samples were furtherly cleaned by hexane washing and acetonitrile precipitation of residual proteins. 3,5-T2 and its isomers 3,3′-T2 and 3′,5′-T2 were then analyzed by HPLC coupled to tandem MS. Accuracy and precision for T2 assay were 88–104% and 95–97%, respectively. Recovery and matrix effect averaged 78% and +8%, respectively. 3,5-T2 was detected in all samples and its concentration averaged (mean ± SEM) 41 ± 5 pg/ml, i.e., 78 ± 9 pmol/l. In the same samples the concentration of 3,3′-T2 averaged 133±15 pg/ml, i.e., 253±29 pmol/l, while 3′,5′-T2 was not detected. 3,5-T2 concentration was significantly related to 3,3′-T2 concentration (r = 0.540, P < 0.01), while no significant correlation was observed with either T3 or T4 in a subset of patients in which these hormones were assayed. In conclusion, our method is able to quantify 3,5-T2 and 3,3′-T2 in human serum. Their concentrations lie in the subnanomolar range, and a significant correlation was detected between these two metabolites in healthy individuals.

To present the first case series of total robotic hysterectomy (TRH), using integrated table motion (ITM), which is a new feature comprising a unique operating table by Trumpf Medical that communicates wirelessly with the da Vinci Xi surgical system. ITM has been specifically developed to improve multiquadrant robotic surgery such as that conducted in colorectal surgery. Between May and October 2015, a prospective post-market study was conducted on ITM in the EU in 40 cases from different specialties. The gynecological study group comprised 12 patients. Primary endpoints were ITM feasibility, safety and efficacy. Ten patients underwent TRH. Mean number of ITM moves was three during TRH; there were 31 instances of table moves in the ten procedures. Twenty-eight of 31 ITM moves were made to gain internal exposure. The endoscope remained inserted during 29 of the 31 table movements (94%), while the instruments remained inserted during 27 of the 31 moves (87%). No external instrument collisions or other problems related to the operating table were noted. There were no ITM safety-related observations and no adverse events. This preliminary study demonstrated the feasibility, safety and efficacy of ITM for the da Vinci Xi surgical system in TRH. ITM was safe, with no adverse events related to its use. Further studies will be useful to define the real role and potential benefit of ITM in gynecological surgery.

Over the past two decades, minimally invasive surgery (MIS) abdominal surgery has increasingly been used to treat pelvic organ prolapse. Besides the several advantages associated with minimal invasiveness, this approach bridged the gap between the benefits of vaginal surgery and the surgical success rates of open abdominal procedures. The most commonly performed procedure for suspension of the vaginal apex for postoperative vaginal prolapse by robotic-assisted laparoscopy is the sacrocolpopexy. Conventional laparoscopic application of this procedure was first reported in 1994 by Nezhat et al. and had not gained widespread adoption due to lengthy learning curve associated with laparoscopic suturing. Since FDA approval of the da Vinci® robot for gynecologic surgery in 2005, minimally invasive abdominal surgery for pelvic organ prolapse has become increasingly popular, as robotic-assisted laparoscopic sacrocolpopexy is an option for those surgeons without experience or training in the conventional route. Robotic surgery has made its way into the armamentarium of POP treatment and has allowed pelvic surgeons to adapt the "gold standard" technique of abdominal sacrocolpopexy to a minimally invasive approach with improved intraoperative morbidity and decreased convalescence. In fact, repair of pelvic organ prolapse can be performed robotically, and sometimes surgeons can feel suturing and dissection during the procedures less challenging with the assistance of the robot. However, even if robotic surgery may confer many benefits over conventional laparoscopy, these advantages should continue to be weighed against the cost of the technology. To date, as long-term outcomes, evidence about robotic sacrocolpopexy for a repair of pelvic organ prolapse are not conclusive, and much more investigations are needed to evaluate subjective and objective outcomes, perioperative and postoperative adverse events, and costs associated with these procedures. It is plausible to think that the main advantage is that robotics may lead to a widespread adoption of minimally invasive techniques in the field of pelvic floor reconstructive surgery. The following review will address the development and current state of robotic assistance in treating pelvic floor reconstruction discussing available data about the techniques of robotic prolapse repair as well as morbidity, costs and clinical outcomes.

Objective To measure serum levels of adipsin, leptin, resistin, adiponectin, visfatin, ghrelin and insulin in postmenopausal women screened for the metabolic syndrome (METS). Methods Serum of 100 postmenopausal women was analyzed using multiplex technology for the mentioned analytes. In addition, values for the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Comparisons were performed in accordance to the presence or not of the METS and each of its components. Criteria of the American Heart Association were used to define the METS. Results Age and time since menopause onset were similar in women with the METS ( n = 57) as compared to those without the syndrome ( n = 43). METS women displayed significantly higher levels of adipsin, leptin, resistin, insulin and HOMA-IR values and lower adiponectin levels. These differences were mainly observed among women with abdominal obesity, independent of fulfilling METS criteria or not. In this same sense, lower adiponectin levels significantly related to low HDL-C and high triglyceride levels; and higher insulin and HOMA-IR values related to high triglyceride and glucose levels, respectively. Conclusion In this sample, postmenopausal women with the METS displayed higher insulin and adipokine levels. These were mainly related to abdominal obesity and metabolic and lipid abnormalities. More research is warranted in this regard.

Background Prevalence of the metabolic syndrome (METS) increases after the menopause; nevertheless, concomitant vascular, inflammatory and endothelial changes have not been completely elucidated. Objective To measure serum markers of angiogenesis, inflammation and endothelial function in postmenopausal women screened for the METS. Methods Serum of 100 postmenopausal women was analyzed for angiopoietin-2, interleukin-8 (IL-8), soluble FAS ligand (sFASL), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), soluble CD40 ligand (sCD40L), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator (uPA). Comparisons were made in accordance to the presence or not of the METS and each of its components. Modified Adult Treatment Panel III criteria were used to define the METS. Results Women with the METS ( n = 57) had similar age and time since menopause as compared to those without the syndrome ( n = 43). In general, women with the METS displayed a trend for higher levels of the analyzed markers. Nevertheless, only IL-6 levels were found to be significantly higher and uPA levels significantly lower among METS women as compared to those without the syndrome. When analyte levels were compared as to presenting or not each of the diagnostic features of the METS, it was found that IL-6 levels were higher among women with abdominal obesity, low HDL-C and high triglyceride levels. Women with low HDL-C and high triglyceride levels presented significantly lower uPA levels and those with high glucose and low HDL-C displayed significantly higher sCD40L levels. Conclusion Postmenopausal women with the METS in this sample displayed higher IL-6 (inflammation) and lower uPA levels (endothelial dysfunction). These were mainly related to metabolic and lipid abnormalities. More research is warranted in this regard.

Menopausal transition results from declining ovarian function and leads to dramatic decreases in estrogens, which turns into a number of disturbances. Because climacteric symptoms result from a decrease in estrogens, it naturally follows that replacing estrogens with hormone replacement therapy (HRT) is effective against menopausal symptoms. HRT is the most effective treatment to reduce the frequency and intensity of hot flushes and vaginal atrophy and positively affects bone loss and risk of fractures. Doubts still linger on the impact of HRT on cardiovascular disease, breast cancer, cognitive impairment, and dementia. Recent data supports the initiation of HRT around the time of menopause to treat menopause-related symptoms and to prevent osteoporosis in women at high risk of fracture. Evidence of a direct link between time since menopause and initiation of HRT has also emerged, which may affect the impact on cardiovascular disease and brain deterioration.

Cardiovascular disease (CVD) has become the leading cause of death for women. The incidence of CVD in women increases substantially with aging, probably because menopause diminishes the gender protection contributing to an adverse impact on cardiovascular risk variables. In this setting, the menopausal transition (MT) must be considered a critical period in women’s life because it leads to several adverse changes, especially with regard to lipid profile and modifies cardiovascular risk factors. Thus, it may be necessary to encourage lifestyle measures and therapeutic interventions such as hormone replacement therapy (HRT) throughout the MT to counteract or prevent these events. HRT for postmenopausal women has been available for more than 60 years. Ever since, HRT has been the subject of discussion and debate regarding its safety and efficacy; nowadays, it is well established that timing in the initiation as well as the type, dose and route of HRT are crucial for the success and benefit of HRT. Furthermore, a new study, published by the British Medical Journal, recently added interesting evidence to this debate, proving that menopausal hormone therapy saves lives and reduces disability.

Estetrol (E4) is a natural human estrogen present at high concentrations during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications. E4 acts as a selective estrogen receptor modulator, exerting estrogenic actions on the endometrium or the central nervous system, while antagonizing the actions of estradiol in the breast. We tested the effects of E4 on its own or in the presence of 17β-estradiol (E2) on T47-D estrogen receptor (ER) positive breast cancer cell migration and invasion of three-dimensional matrices. E4 administration to T47-D cells weakly stimulated migration and invasion. However, E4 decreased the extent of movement and invasion induced by E2. Breast cancer cell movement requires a remodeling of the actin cytoskeleton. During exposure to E4, a weak, concentration-dependent, redistribution of actin fibers towards the cell membrane was observed. However, when E4 was added to E2, a inhibition of actin remodeling induced by E2 was seen. Estrogens stimulate ER+ breast cancer cell movement through the ezrin-radixin-moesin (ERM) family of actin regulatory proteins, inducing actin and cell membrane remodeling. E4 was a weak inducer of moesin phosphorylation on Thr558, which accounts for its functional activation. In co-treatment with E2, E4 blocked the activation of this actin controller in a concentration-related fashion. These effects were obtained through recruitment of ERα. In conclusion, E4 acted as a weak estrogen on breast cancer cell cytoskeleton remodeling and movement. However, when E2 was present, E4 counteracted the stimulatory actions of E2. This contributes to the emerging hypothesis that E4 may be a naturally occurring estrogen receptor modulator in the breast.

Reproductive age in women is characterized by several different phases, which constitute a unique endocrinologic continuum. It starts with the beginning of fertile life, with regular, cyclic menses, typical of ovulatory cycles, and it ends with a concluding menstrual period, due to final ovarian senescence, indicated as the menopause. An important moment in this complex process is represented by the menopausal transition, the time period in the late reproductive years, which usually begins with menstrual irregularity and persists until 1 year after last menses. The menopausal transition typically starts in the late 40s or early 50s and continues for about 4–7 years. This is a time of complex and integrated endocrine change that affect the development of symptoms and should drive the choice of appropriate therapies. Fil: Palla, Giulia. Università di Pisa; Italia Fil: Spina, Stefania. Università di Pisa; Italia Fil: Bernacchi, Guja. Università di Pisa; Italia Fil: Cecchi, Elena. Università di Pisa; Italia Fil: Di Bello, Silvia. Università di Pisa; Italia Fil: Pisaneschi, Silvia. Università di Pisa; Italia Fil: Montt Guevara, Maria Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Università di Pisa; Italia Fil: Campelo, Adrián Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; Argentina. Università di Pisa; Italia Fil: de Tommaso, Daniela Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Università di Pisa; Italia

The climacteric syndrome is a complex condition characterized by a set of symptoms and degenerative changes that ensue due to the decline in production of sex steroids by the ovaries. This set of changes identifies women at additional risk of degenerative changes during ageing and calls for personalized interventions. Hence, there is a need for safe methods for the short- and long-term management of postmenopausal women. Hormone replacement therapy (HRT) is widely used for the relief of menopausal symptoms and for the prevention of diseases linked to long-term hormonal deprivation. The use of HRT has increased rapidly in the past decade but is currently a subject of debate because of the possible negative effects on the breast. Other molecules have been studied as alternatives to standard hormonal replacement therapy to relief the symptoms also in women with contraindications to hormones or who refuse sex steroids for personal reasons. The aim of this chapter is to discuss the results of the principal studies performed in these last few years on the safety of HRT and of other climacteric therapies and to suggest how to personalize therapies in climacteric women.

The female pelvic floor is a complex functional unit involved in many undertakings. Pelvic floor dysfunction affects micturition, defecation, and sexual activity. Evolutionary adaptation, such as the acquisition of the upright standing position, walking, and delivery of fetuses with larger head diameters, made the fascial and the muscle support of the pelvic floor more vulnerable, predisposing women to pelvic organ prolapse and incontinence. In addition, the female pelvic floor (differently than in males) undergoes a number of adaptive changes related to life and endocrine events. Many of these clinical manifestations become apparent after menopause and aging in women. This chapter summarizes the key aspects of the pathophysiology and the clinics of the changes of the pelvic floor in women, in particular focusing on the association between endocrine changes of aging women and urinary problems and bowel dysfunctions. Fil: Pisaneschi, Silvia. Universitá di Pisa; Italia Fil: Palla, Giulia. Universitá di Pisa; Italia Fil: Spina, Stefania. Universitá di Pisa; Italia Fil: Bernacchi, Guja. Universitá di Pisa; Italia Fil: Cecchi, Elena. Universitá di Pisa; Italia Fil: Di Bello, Silvia. Universitá di Pisa; Italia Fil: Montt Guevara, Maria Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universitá di Pisa; Italia Fil: Campelo, Adrián Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; Argentina. Università di Pisa; Italia Fil: Simoncini, Tommaso. Universitá di Pisa; Italia